Abstract
BackgroundMajor human gastrointestinal pathogen Helicobacter pylori (H. pylori) colonizes the gastric mucosa causing inflammation and severe complications including cancer, but the involvement of fibroblasts in the pathogenesis of these disorders in H. pylori‐infected stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts. Their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue; however, the interaction between H. pylori and fibroblasts remains unknown. We determined the effect of coincubation of normal rat gastric fibroblasts with alive H. pylori (cagA+vacA+) and H. pylori (cagA−vacA−) strains on the differentiation of these fibroblasts into cells possessing characteristics of cancer‐associated fibroblasts (CAFs) able to induce epithelial‐mesenchymal transition (EMT) of normal rat gastric epithelial cells (RGM‐1).Materials and MethodsThe panel of CAFs markers mRNA was analyzed in H. pylori (cagA+vacA+)‐infected fibroblasts by RT‐PCR. After insert coculture of differentiated fibroblasts with RGM‐1 cells from 24 up to 48, 72, and 96 hours, the mRNA expression for EMT‐associated genes was analyzed by RT‐PCR.ResultsThe mRNA expression for CAFs markers was significantly increased after 72 hours of infection with H. pylori (cagA+vacA+) but not H. pylori (cagA−vacA−) strain. Following coculture with CAFs, RGM‐1 cells showed significant decrease in E‐cadherin mRNA, and the parallel increase in the expression of Twist and Snail transcription factors mRNA was observed along with the overexpression of mRNAs for TGFβR, HGFR, FGFR, N‐cadherin, vimentin, α‐SMA, VEGF, and integrin‐β1.Conclusion Helicobacter pylori (cagA+vacA+) strain induces differentiation of normal fibroblasts into CAFs, likely to initiate the EMT process in RGM‐1 epithelial cell line.
Highlights
Despite the incidence and mortality of gastric cancer (GC) have been decreasing, this disorder still remains one of the leading causes of cancer-related death rate worldwide.[1,2,3,4] Despite the fact that the adjuvant chemotherapy and surgical resection are the only curative therapies nowadays, most patients are diagnosed with an advanced stage of disease due to lack of specific early symptoms
The increased fibroblasts to myofibroblasts differentiation with increased collagen production, the alteration in proliferation, and apoptosis were implicated in the mechanism of interaction between fibroblasts and H. pylori.[10]
It has been demonstrated that further transformation of myofibroblasts and fibroblasts into cancer-associated fibroblasts (CAFs) as well as the interactions between the neoplastic and non-neoplastic cells with the extracellular matrix (ECM) leads to the extensive desmoplastic reaction
Summary
Despite the incidence and mortality of gastric cancer (GC) have been decreasing, this disorder still remains one of the leading causes of cancer-related death rate worldwide.[1,2,3,4] Despite the fact that the adjuvant chemotherapy and surgical resection are the only curative therapies nowadays, most patients are diagnosed with an advanced stage of disease due to lack of specific early symptoms. The proinflammatory factors released by CAFs, such as IL-6, COX-2 and CXCL1, FSP1, CXCL9, CXCL10 (IP-10), and CXCL12 (SDF-1 stromal cell-derived factor 1), were implicated in the mechanism of tumor growth and neoplastic cell invasion.[35,36,37,38,39] The CAFs secrete proangiogenic factors, such as IL-8, SDF-1, vascular endothelial factor (VEGF), and fibroblast growth factor (FGF), into an environment of other stromal cells including endothelial cells to promote tumor angiogenesis.[30,35,38,39] CAFs may enhance invasion of the cancer cells through expression of TGF β, potent EMT inducer, and HGF, which has been shown to promote breast tumorigenesis.[39,40] Since fibroblasts may alter the mRNA expression of structural and cell cycle-associated genes in the presence of H. pylori,[9,41] we have attempted to determine whether H. pylori can interact with fibroblasts by changing them into myofibroblasts, and into CAFs, further being capable of inducing EMT program in normal RGM-1 epithelial cell line
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